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    New biomarkers for ovarian cancer: OVA1 and ROMA in diagnosis

    Selective use of these new tests may lead to better outcomes for women with adnexal masses or epithelial ovarian cancer

    The optimal management of a woman with an ovarian adnexal mass remains a clinical challenge to obstetricians, gynecologists, and other providers who care for women. Although after surgical evaluation many such masses ultimately are found to be benign, a woman with a malignant mass will need referral to a gynecologic oncologist for possible further surgical staging and determination for potential adjuvant therapy.

    The clinical burden of ovarian cancer on patients, their families, and the US healthcare system cannot be underestimated. Unfortunately, less than half of all women with such malignancies are cared for by gynecologic oncologists, despite data supporting the improved outcome of women with ovarian cancer when they are evaluated and treated by a specialist in their care.1-3

    CA125: an imperfect tool

    The serum biomarker CA125 has for decades remained one of the primary diagnostic tools, along with pelvic imaging, in the preoperative management of women with pelvic masses. CA125 is expressed in epithelial tissues, including the mesothelial cells of the pleura and peritoneum and the müllerian cells of the fallopian tube, endometrium, and endocervix.4

    CA125 is not expressed by the surface epithelium of normal ovaries. Elevated CA125 levels in women with metastatic epithelial ovarian cancer, however, have led to the widespread adoption of this serum test as a potential marker of malignancy in women with a pelvic mass.

    Unfortunately, the sensitivity and specificity of CA125 in predicting malignancy, along with the positive predictive value, remain low—approximately 50% of women with stage I epithelial ovarian cancers will have a normal CA125 level preoperatively. Further, several conditions, including malignancies of other abdominal organs and a number of benign conditions, will result in elevated levels.5

    Developing novel biomarkers

    There has been significant effort in the research and development of novel biomarkers applicable to the diagnosis and management of epithelial ovarian cancer. Several preliminary studies examining multiple novel biomarkers in addition to CA125 have led to initial enthusiasm.6-8 These include the OvaSure serum test, which includes examination of leptin, prolactin, osteopontin, insulin-like growth factor-II, macrophage inhibitory factor, and CA125, as well as the OvaCheck test, which involves proteomic profile analysis of serum proteins. Unfortunately, the lack of validation studies has precluded their effectiveness as screening tests for ovarian cancer in otherwise asymptomatic women.

    In contrast, new data examining additional biomarkers in women with a known pelvic mass have led to the development and validation of novel strategies that can be used in the clinical care of these patients.

    Referral guidelines

    In 2002, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) jointly published referral guidelines to assist the gynecologist in the triage of women with pelvic masses.9

    For premenopausal women (<50 years), 2002 criteria included a CA125 level more than 200 U/mL, the presence of ascites, evidence of abdominal or distant metastasis (by exam or imaging), and a family history of breast or ovarian cancer (in a first-degree relative).

    For postmenopausal women (=50 years), criteria included a CA125 level of more than 35 U/mL, the presence of ascites, the presence of a nodular or fixed pelvic mass, evidence of abdominal or distant metastasis (by exam or imaging), and a family history of breast or ovarian cancer (in a first-degree relative). Only 1 criterion was required to recommend referral to a gynecologic oncologist.

    Although the guidelines are evidence based, validation of their effectiveness in distinguishing cancers from benign masses was not established until researchers reported on a retrospective review of 1,035 patients from 7 tertiary centers during a 12-month interval.10 They determined that the referral guidelines captured 70% of the ovarian cancers in the premenopausal group and 94% in the postmenopausal group, with positive predictive values of 33.8% and 59.5%, respectively. The negative predictive values were more than 90% for both groups.

    Further validation in a prospective population was performed by researchers who studied 837 patients over a 5-year period and reported that the referral guidelines demonstrated a sensitivity of 79.2% for identifying ovarian cancer in the premenopausal group and 93.2% in the postmenopausal group.11 They also determined similar positive predictive values for the 2 groups (39.6% and 64.6%, respectively).



    Both studies found that a family history of breast or ovarian cancer in either group and the presence of a fixed or nodular mass in the postmenopausal group did not contribute to the performance of the referral guidelines. Furthermore, both studies reported that lowering the CA125 threshold level in the premenopausal group to either 50 U/mL or 67 U/mL —depending on the study—significantly improved the sensitivity of the guidelines.

    Updated ACOG guidelines


    TABLE 1 2011 ACOG/SGO referral guidelines for women with a pelvic mass
    On the basis of these data, ACOG modified its referral guidelines in 2011.12 The new guidelines omit the family history criterion altogether and the presence of a fixed or nodular mass in premenopausal women. Furthermore, the CA125 threshold level is now less clearly defined. Again, the presence of at least 1 of the new criteria warrants consideration of referral or consultation with a gynecologic oncologist in women with a suspicious pelvic mass (Table 1).12

    For premenopausal women, the criteria now include a very elevated CA125 level, ascites, or evidence of abdominal or distant metastasis. For postmenopausal women, these include an elevated CA125 level, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis. Based on clinical studies, a CA125 level greater than 50 U/mL in postmenopausal women could be considered very elevated, and a level greater than 35 U/mL considered an elevated level.10,11

    OVA1: sensitivity-specificity tradeoff

    The US Food and Drug Administration (FDA) has recently approved for marketing a novel qualitative serum test to assist in the prediction of ovarian cancer in women with pelvic masses.13 This multivariate index assay, known as OVA1, examines 5 biomarkers: transthyretin, apolipoprotein, A-1, 2-microglobulin, transferrin, and CA125. The levels of these 5 proteins are measured using 2 different immunoassay platforms (Roche Diagnostics' Elecsys 2010 for CA125 and Siemens Healthcare Diagnostics' BNII System for the others), which are subsequently interpreted by the proprietary OvaCalc software.14 This software involves a multivariate index assay algorithm to generate a score that is considered high probability or low probability for malignancy. For premenopausal women, a score of 5.0 or higher is considered high probability; for postmenopausal women, a score of 4.4 or higher is high probability.

    OVA1 has now been evaluated prospectively in a multi-institutional study examining 590 women scheduled for surgery for a pelvic mass.14 All enrolling physicians (gynecologists, gynecologic oncologists, and nongynecologic oncologists) reported their preoperative assessment of malignancy (considered as yes or no) on the basis of preoperative information, excluding the results of the OVA1 test.

    After surgery, 151 ovarian malignancies were identified, and most were epithelial cancers.14 The researchers reported that OVA1 was more sensitive in detecting ovarian cancers than either clinician assessment (regardless of specialty training) or CA125 alone. Adding OVA1 to a physician assessment correctly identified 70% of cancers missed by gynecologists and 95% of cancers missed by gynecologic oncologists. Furthermore, OVA1 demonstrated 100% sensitivity for ovarian cancers stages II through IV; for stage I disease, sensitivity was 90% for OVA1, compared with 61% for CA125.

    In contrast, the specificity and positive predictive value of OVA1 with physician assessment was worse when compared with CA125 alone.14 Two hundred and sixty-one benign tumors were referred to the gynecologic oncologist for surgery, with a referral rate for nonmalignant disease of 72%. Additional limitations of this study included a lack of a uniform preoperative evaluation and that all women enrolled in the trial were already scheduled for surgery; because the prevalence of cancer in this cohort is high, this latter factor may reflect a higher positive predictive value and lower negative predictive value than a group of women in whom surveillance would be favored.

    Despite relatively minor limitations, the strengths of this study have led to the widespread availability of OVA1 testing. In order to determine whether this multivariate index assay can improve preoperative assessment of malignancy in women with pelvic masses in the context of existing clinical algorithms, the OVA1 investigators estimated the performance of the ACOG ovarian tumor referral guidelines using the results of this multivariate index assay in place of CA125.15

    In the same cohort of 590 women, investigators identified a statistically improved sensitivity (94% with OVA1 vs 77% with CA125) and negative predictive value (93% with OVA1 vs 87% with CA125) but found decreased specificity (35% vs 68%) and positive predictive value (40% vs 52%).15 The high sensitivity and negative predictive value was maintained in premenopausal women and in those with early stage ovarian cancers. A significantly higher proportion of cancers missed using CA125 in the referral guidelines were found when OVA1 was examined.


    TABLE 2 Simplified referral guidelines for women (of any age) with a pelvic mass
    On the basis of these data, the researchers suggest a further modification of the ACOG referral guidelines for women with an ovarian adnexal mass.15 Family history appears to be of marginal significance in the assessment of malignancy, and the OVA1 test incorporates menopausal status in its result. The investigators recommend simplified referral criteria for a woman of any age with a pelvic mass (Table 215 ): nodular or fixed pelvic mass on examination; ascites; evidence of abdominal or distant metastasis on imaging; multivariate index assay test positive. Again, any 1 criterion would warrant referral to a gynecologic oncologist, and the clinical performance of this simplified algorithm has a sensitivity of 93%, specificity of 40%, positive predictive value of 41%, and negative predictive value of 93%.

    A valid concern of many obstetricians and gynecologists is the decrease in specificity with the OVA1 test, which may imply that a greater proportion of women with nonmalignant tumors would be referred to gynecologic oncologists.

    However, lowered specificity may not necessarily result in a high number of benign masses that would then be surgically removed by a specialist. The improved negative predictive value of the ACOG referral guidelines including OVA1 could decrease referrals because women with a negative test are more likely to have benign disease.

    In addition, the OVA1 investigators reported that in their cohort, 72% of 355 women with benign ovarian masses were referred to gynecologic oncologists for treatment despite 45% of the referring obstetrician/gynecologists reporting a preoperative assessment of a benign tumor.15 Referral to a specialist is a complex process that reflects several variables, and historically between 60% and 80% of all patients undergoing surgery by a gynecologic oncologist will have benign disease. The actual effect of OVA1 testing on patient referral patterns remains to be determined.

    HE4 and the algorithm for risk of ovarian malignancy

    In addition to the novel proteins incorporated into the OVA1 test, HE4 (human epididymis protein 4) is an additional new FDA-approved biomarker for use in managing women with an ovarian adnexal mass.

    HE4 is a protease inhibitor expressed by malignant epithelial ovarian cells that is also measurable in the serum of women with ovarian cancer.16 The FDA approved the use of HE4 in 2008 for monitoring women with a history of ovarian cancer, and recent efforts examining HE4 in combination with CA125 led to the development of a logistic regression model incorporating menopausal status with the serum levels of these 2 biomarkers in the evaluation of women with a pelvic mass.


    TABLE 2 Simplified referral guidelines for women (of any age) with a pelvic mass
    This Risk of Ovarian Malignancy Algorithm (ROMA) classifies these patients into high-risk or low-risk groups for having epithelial ovarian cancer. The ROMA score reflects a predictive index calculated by equations that differ based on the patient's menopausal status. The ROMA score is then calculated from the predictive index (Table 3).17 Calculators are available online (www.southeastasia.abbottdiagnostics.com and www.he4test.com/), where scores are calculated based on entered CA125 and HE4 values; a smartphone application is also available.

    The results of a prospective, multi-institutional study of 531 patients initially validated this model.18 Researchers describe a sensitivity of 92% and 76% (for postmenopausal and premenopausal women, respectively), with a specificity of 75%. The positive predictive values were 33.8% (premenopausal women) and 74.0% (postmenopausal women); the negative predictive values were 95.0% and 92.6%, respectively. It is important to note that this cohort was considered high-risk because patients were recruited after seeing a gynecologic oncologist, and thus the prevalence of actual cancer was high, potentially influencing the high sensitivities identified.

    To validate this model further, in a low-risk population of women with an adnexal mass who saw a gynecologist, family practitioner, internist, or general surgeon, the investigators performed a second prospective multi-institutional study of 472 women.19 In this study, the incidence of ovarian cancer was 10% compared with 24% in the previous trial. In the low-risk cohort, the sensitivity of ROMA was 92% and the specificity 76% in postmenopausal women, and 100% and 74%, respectively, in premenopausal women. When evaluating the entire cohort regardless of age, the negative predictive value was 99%.

    On an international level, ROMA has been evaluated and validated by different cohorts in Italy and Belgium. The Italian trial represented a high-risk population, with about half the 104 women enrolled having epithelial ovarian cancer; similar sensitivities and specificities as in the US studies were identified.17 In the Belgian trial of 389 patients, 41% were found to have ovarian cancer; thus, the cohort is also considered high-risk; high sensitivities and specificities also were reported.20 On the basis of these data in high-risk and low-risk populations, FDA in 2011 approved the use of HE4 and CA125 using ROMA to determine the risk of ovarian cancer in women with a pelvic mass.21

    Comparisons between the efficacy of OVA1 and ROMA are natural after the recent approvals of these novel tools and the clinical availability and applicability of either test. Two factors may promote the use of ROMA: specificity and cost. The lower specificity of OVA1 compared with ROMA may be problematic because a greater number of referrals (including those women who will ultimately be found to have a benign pelvic mass) would be sent to gynecologic oncologists for surgical procedures.

    Although the OVA1 investigators have addressed this, routine use of the OVA1 test may promote an increase in referral rates. Furthermore, cost of the test is a valid concern. Currently, the only laboratory licensed to perform the OVA1 test charges approximately $600. In comparison, CA125 and HE4 testing, which may be performed by any laboratory via multiple FDA-approved assays, costs approximately $100. Although insurers have so far reimbursed for the OVA1 test, changes that result in greater out-of-pocket expenses by patients may influence the choice of testing.

    New tools may facilitate better outcomes

    Several advances in biomarker discovery and development have now led to additional tools that may be useful in the clinical management of women with adnexal masses, with recent FDA approval of both a multivariate index assay examining 5 novel biomarkers (OVA1) and a risk of ovarian cancer algorithm studying CA125 and HE4 (ROMA).

    Despite the differences in cost and specificity, selective use of these new tests may aid in the preoperative management of women with pelvic masses. Although neither test can or should be used for screening otherwise asymptomatic women, these tools reflect the significant efforts in research and study validation that may lead to better outcomes for women with benign masses and for those with epithelial ovarian cancer.

    DR. LI is Co-Director of the Women's Reproductive Cancer Centers of Excellence at Cedars-Sinai Medical Center and Associate Professor of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California. He has no conflicts of interest to disclose with respect to this article.

    REFERENCES

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    2. Bristow RE, Palis BE, Chi DS, Cliby WA. The National Cancer Database report on advanced-stage epithelial ovarian cancer: impact of hospital surgical case volume on overall survival and surgical treatment paradigm. Gynecol Oncol. 2010;118(3):262-267.

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    8. Petricoin EF, Ardekani AM, Hitt BA, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet. 2002;359(9306):572-577.

    9. American College of Obstetricians and Gynecologists. ACOG Committee Opinion: number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol. 2002;100(6):1413-1416.

    10. Im SS, Gordon AN, Buttin BM, et al. Validation of referral guidelines for women with pelvic masses. Obstet Gynecol. 2005;105(1):35-41.

    11. Dearking AC, Aletti GD, McGree ME, Weaver AL, Sommerfield MK, Cliby WA. How relevant are ACOG and SGO guidelines for referral of adnexal mass? Obstet Gynecol. 2007;110(4):841-848.

    12. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet Gynecol. 2011;117(3):742-746.

    13. US Food and Drug Administration. FDA clears a test for ovarian cancer [press release]. September 11, 2009. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm182057.htm. Accessed March 2, 2012.

    14. Ueland FR, Desimone CP, Seamon LG, et al. Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. Obstet Gynecol. 2011;117(6):1289-1297.

    15. Ware Miller R, Smith A, DeSimone CP, et al. Performance of the American College of Obstetricians and Gynecologists' ovarian tumor referral guidelines with a multivariate index assay. Obstet Gynecol. 2011;117(6):1298-1306.

    16. Hellstrom I, Raycraft J, Hayden-Ledbetter M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63(13):3695-3700.

    17. Montagnana M, Danese E, Ruzzenente O, et al. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? Clin Chem Lab Med. 2011;49(3):521-525.

    18. Moore RG, McMeekin DS, Brown AK, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009;112(1):40-46.

    19. Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118(2 pt 1):280-288.

    20. Van Gorp T, Cadron I, Despierre E, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Brit J Cancer. 2011:104(5):863-870.

    21. US Food and Drug Administration. Premarket notification. 510(k) Summary. http://www.accessdata.fda.gov/cdrh_docs/pdf10/K103358.pdf|~http://www.accessdata.fda.gov/cdrh_docs/pdf10/K103358.pdf . Accessed March 16, 2012.

    Andrew John Li, MD
    Dr. Li is a Fellow in Gynecologic Oncology

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